CAR T-cell Therapy for Glioblastoma
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: University of Pennsylvania
Must not be taking: Immunosuppressants, Bevacizumab
Disqualifiers: Hepatitis, Cardiovascular, Autoimmune, others
No Placebo Group
Approved in 1 Jurisdiction
Trial Summary
What is the purpose of this trial?This is an open-label phase 1 study to assess the safety and feasibility of autologous T cells co-expressing two CARs targeting the cryptic EGFR and IL13Ra2 (referred to as "CART-EGFR-IL13Ra2 cells") in patients with EGFR-amplified glioblastoma, IDH-wildtype that has recurred following prior radiotherapy.
Do I need to stop my current medications for the trial?
The trial protocol does not specify if you need to stop taking your current medications. However, if you are on bevacizumab, you must not have received it within 3 months before eligibility confirmation.
What data supports the effectiveness of the treatment CART-EGFR-IL13Ra2 Cells for glioblastoma?
Research shows that CAR T-cell therapy targeting IL13Rα2, a protein found in glioblastoma but not in normal brain tissue, can lead to tumor regression and improved survival in animal models and a patient case study. This suggests that CART-EGFR-IL13Ra2 Cells could be effective in treating glioblastoma by specifically targeting cancer cells without affecting healthy brain cells.
12345Is CAR T-cell therapy for glioblastoma safe for humans?
Research shows that CAR T-cell therapy targeting IL13Rα2 in glioblastoma patients has not been associated with severe toxic effects, indicating it is generally safe in humans.
12367What makes the CAR T-cell therapy for glioblastoma unique?
This treatment uses specially engineered T cells to target a protein called IL13Rα2, which is found on glioblastoma cells but not on normal brain cells, making it a precise and promising approach for attacking the tumor without harming healthy tissue.
12358Eligibility Criteria
This trial is for adults over 18 with recurrent glioblastoma, IDH-wildtype, after radiotherapy. Candidates must have adequate organ function, EGFR-amplified tumors confirmed by specific tests, and agree to use birth control. Excluded are those with active hepatitis B/C, severe comorbidities, recent bevacizumab treatment, autoimmune diseases needing high-dose steroids or pregnant/nursing women.Inclusion Criteria
My glioblastoma has returned after radiation treatment.
I am 18 years old or older.
Subjects of reproductive potential must agree to use acceptable birth control methods
+10 more
Exclusion Criteria
I am allergic to some ingredients in the study medication.
I have not received bevacizumab in the last 3 months.
I have an active hepatitis B or C infection.
+6 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive a single fixed dose of CART-EGFR-IL13Ra2 cells via intrathecal administration on Day 0, with dose escalation based on cohort assignment
4 weeks
1 visit (in-person) for administration, followed by staggered monitoring
Follow-up
Participants are monitored for safety and effectiveness after treatment, with formal DLT evaluations performed after the 3rd subject in each cohort reaches the Day 28 safety follow-up visit
4 weeks
1 visit (in-person) for safety follow-up
Long-term follow-up
Participants are monitored for progression-free survival and objective response rate over an extended period
15 years
Participant Groups
The study is testing the safety of CART-EGFR-IL13Ra2 cells in patients whose glioblastoma has returned despite prior treatments. It's an early-phase trial where participants receive genetically modified T cells targeting two specific molecules on their cancer.
4Treatment groups
Experimental Treatment
Group I: Dose Level 3Experimental Treatment1 Intervention
Cohort 3 (N = 3-6): will receive a single fixed dose of 5x10\^7 CART-EGFR-IL13Ra2 cells via intrathecal administration on Day 0.
Group II: Dose Level 2Experimental Treatment1 Intervention
Cohort 2 (N = 3-6): will receive a single fixed dose of 2.5x10\^7 CART-EGFR-IL13Ra2 cells via intrathecal administration on Day 0.
Group III: Dose Level 1Experimental Treatment1 Intervention
Cohort 1 (N = 3-6): will receive a single fixed dose of 1x10\^7 CART-EGFR-IL13Ra2 cells via intrathecal administration on Day 0.
Group IV: Dose Level -1Experimental Treatment1 Intervention
Cohort-1 (N = 3-6): will receive a single fixed dose of 5x10\^6 CART-EGFR-IL13Ra2 cells via intrathecal administration on Day 0.
CART-EGFR-IL13Ra2 Cells is already approved in United States for the following indications:
🇺🇸 Approved in United States as CART-EGFR-IL13Ra2 for:
- Glioblastoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of PennsylvaniaPhiladelphia, PA
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Who Is Running the Clinical Trial?
University of PennsylvaniaLead Sponsor
Tmunity TherapeuticsIndustry Sponsor
Gilead SciencesIndustry Sponsor
Tmunity Therapeutics, a wholly owned subsidiary of Kite Pharma (a Gilead company)Collaborator
References
Characterization and Functional Analysis of scFv-based Chimeric Antigen Receptors to Redirect T Cells to IL13Rα2-positive Glioma. [2018]Immunotherapy with T cells expressing chimeric antigen receptors (CARs) is an attractive approach to improve outcomes for patients with glioblastoma (GBM). IL13Rα2 is expressed at a high frequency in GBM but not in normal brain, making it a promising CAR T-cell therapy target. IL13Rα2-specific CARs generated up to date contain mutated forms of IL13 as an antigen-binding domain. While these CARs target IL13Rα2, they also recognize IL13Rα1, which is broadly expressed. To overcome this limitation, we constructed a panel of IL13Rα2-specific CARs that contain the IL13Rα2-specific single-chain variable fragment (scFv) 47 as an antigen binding domain, short or long spacer regions, a transmembrane domain, and endodomains derived from costimulatory molecules and CD3.ζ (IL13Rα2-CARs). IL13Rα2-CAR T cells recognized IL13Rα2-positive target cells in coculture and cytotoxicity assays with no cross-reactivity to IL13Rα1. However, only IL13Rα2-CAR T cells with a short spacer region produced IL2 in an antigen-dependent fashion. In vivo, T cells expressing IL13Rα2-CARs with short spacer regions and CD28.ζ, 41BB.ζ, and CD28.OX40.ζ endodomains had potent anti-glioma activity conferring a significant survival advantage in comparison to mice that received control T cells. Thus, IL13Rα2-CAR T cells hold the promise to improve current IL13Rα2-targeted immunotherapy approaches for GBM and other IL13Rα2-positive malignancies.
Chimeric Antigen Receptor T Cells With Modified Interleukin-13 Preferentially Recognize IL13Rα2 and Suppress Malignant Glioma: A Preclinical Study. [2021]Interleukin-13 receptor α 2 (IL13Rα2) is a promising tumor-directed antigen of malignant glioma (MG). Here, we examine the efficacy and safety of T cells containing a YYB-103 chimeric antigen receptor (CAR) that can preferentially bind to IL13Rα2 on MG cells.
Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. [2023]A patient with recurrent multifocal glioblastoma received chimeric antigen receptor (CAR)-engineered T cells targeting the tumor-associated antigen interleukin-13 receptor alpha 2 (IL13Rα2). Multiple infusions of CAR T cells were administered over 220 days through two intracranial delivery routes - infusions into the resected tumor cavity followed by infusions into the ventricular system. Intracranial infusions of IL13Rα2-targeted CAR T cells were not associated with any toxic effects of grade 3 or higher. After CAR T-cell treatment, regression of all intracranial and spinal tumors was observed, along with corresponding increases in levels of cytokines and immune cells in the cerebrospinal fluid. This clinical response continued for 7.5 months after the initiation of CAR T-cell therapy. (Funded by Gateway for Cancer Research and others; ClinicalTrials.gov number, NCT02208362 .).
Receptor for interleukin 13 is abundantly and specifically over-expressed in patients with glioblastoma multiforme. [2020]We have recently documented that the vast majority of patients with glioblastoma multiforme (GBM) over-express a receptor (R) for interleukin 13 (IL13) in situ. We have now evaluated further the degree of relative specificity of the binding of IL13 to GBM when compared with other growth factor receptors. Tumor samples of 11 patients with GBM, 7 various normal brain samples, and several cell lines in culture were examined. Same patient tissue sections were incubated with 125I-labeled: IL13, monoclonal antibody HB21 against human transferrin (Tf) receptor, epidermal growth factor (EGF), and an IL4 antagonist, IL4.Y124D. All 11 GBMs stained specifically, densely, and relatively homogeneously for both IL13R and TfR. Seven GBM specimens showed specific binding for 125I-EGF, but it was less homogeneous when compared with IL13R or TfR. Two of the GBMs studied demonstrated extremely high density of the EGFR. Furthermore, we did not detect significant presence of the IL4R in the studied GBM specimens in situ. All sections of non-malignant brain tissues examined showed avid binding by the TfR with lack of consistent and specific binding of 125I-IL13 or -EGF. Thus, it appears that the GBM-associated IL13R is considerably more specific to GBM that the one for Tf and more frequently and homogeneously expressed than the EGFR. These results render further support for the hIL13R being a new unique candidate for delivery of variety of anti-GBM therapies.
Suppression of human glioma xenografts with second-generation IL13R-specific chimeric antigen receptor-modified T cells. [2021]Glioblastoma multiforme (GBM) remains highly incurable, with frequent recurrences after standard therapies of maximal surgical resection, radiation, and chemotherapy. To address the need for new treatments, we have undertaken a chimeric antigen receptor (CAR) "designer T cell" (dTc) immunotherapeutic strategy by exploiting interleukin (IL)13 receptor α-2 (IL13Rα2) as a GBM-selective target.
Checkpoint Blockade Reverses Anergy in IL-13Rα2 Humanized scFv-Based CAR T Cells to Treat Murine and Canine Gliomas. [2020]We generated two humanized interleukin-13 receptor α2 (IL-13Rα2) chimeric antigen receptors (CARs), Hu07BBz and Hu08BBz, that recognized human IL-13Rα2, but not IL-13Rα1. Hu08BBz also recognized canine IL-13Rα2. Both of these CAR T cell constructs demonstrated superior tumor inhibitory effects in a subcutaneous xenograft model of human glioma compared with a humanized EGFRvIII CAR T construct used in a recent phase 1 clinical trial (ClinicalTrials.gov: NCT02209376). The Hu08BBz demonstrated a 75% reduction in orthotopic tumor growth using low-dose CAR T cell infusion. Using combination therapy with immune checkpoint blockade, humanized IL-13Rα2 CAR T cells performed significantly better when combined with CTLA-4 blockade, and humanized EGFRvIII CAR T cells' efficacy was improved by PD-1 and TIM-3 blockade in the same mouse model, which was correlated with the levels of checkpoint molecule expression in co-cultures with the same tumor in vitro. Humanized IL-13Rα2 CAR T cells also demonstrated benefit from a self-secreted anti-CTLA-4 minibody in the same mouse model. In addition to a canine glioma cell line (J3T), canine osteosarcoma lung cancer and leukemia cell lines also express IL-13Rα2 and were recognized by Hu08BBz. Canine IL-13Rα2 CAR T cell was also generated and tested in vitro by co-culture with canine tumor cells and in vivo in an orthotopic model of canine glioma. Based on these results, we are designing a pre-clinical trial to evaluate the safety of canine IL-13Rα2 CAR T cells in dog with spontaneous IL-13Rα2-positive glioma, which will help to inform a human clinical trial design for glioblastoma using humanized scFv-based IL-13Rα2 targeting CAR T cells.
Stem-like tumor-initiating cells isolated from IL13Rα2 expressing gliomas are targeted and killed by IL13-zetakine-redirected T Cells. [2022]To evaluate IL13Rα2 as an immunotherapeutic target for eliminating glioma stem-like cancer initiating cells (GSC) of high-grade gliomas, with particular focus on the potential of genetically engineered IL13Rα2-specific primary human CD8(+) CTLs (IL13-zetakine(+) CTL) to target this therapeutically resistant glioma subpopulation.
T cells redirected to interleukin-13Rα2 with interleukin-13 mutein--chimeric antigen receptors have anti-glioma activity but also recognize interleukin-13Rα1. [2021]Outcomes for patients with glioblastoma remain poor despite aggressive multimodal therapy. Immunotherapy with genetically modified T cells expressing chimeric antigen receptors (CARs) targeting interleukin (IL) 13Rα2, human epidermal growth factor receptor 2, epidermal growth factor variant III or erythropoietin-producing hepatocellular carcinoma A2 has shown promise for the treatment of glioma in preclinical models. On the basis of IL13Rα2 immunotoxins that contain IL13 molecules with one or two amino acid substitutions (IL13 muteins) to confer specificity to IL13Rα2, investigators have constructed CARS with IL13 muteins as antigen-binding domains. Whereas the specificity of IL13 muteins in the context of immunotoxins is well characterized, limited information is available for CAR T cells.